Gene Promoter Methylation and Its Potential Relevance in Early Prostate Cancer Diagnosis

Abstract

Aims: We investigated hypermethylation of the glutathione S-transferase pi (GSTP1), retinoic acid receptor β2 (RARβ2), adenomatous polyposis coli (APC) and paired-like homeodomain transcription factor 2 (PITX2) gene promoters which could serve as a sensitive tool to indicate a risk of prostate cancer even in histologically tumor-free tissues. Methods: Tumor tissues and non-neoplastic tissues at variable distances from the tumor foci were retrieved from 25 formalin-fixed and paraffin-embedded prostatectomy specimens and subjected to DNA extraction. The methylation levels were assessed by means of different assay technologies. Results: Significantly increased methylation levels in cancer specimens were found for all promoter regions (GSTP1: 21/25, 84%; RARβ2: 24/25, 96%; APC: 21/25, 84%; PITX2: 20/25, 80%) and in most samples containing prostatic intraepithelial neoplasia. Several samples showed increased RARβ2 and APC methylation in adjacent non-neoplastic tissue. An association between the methylation extent of GSTP1, APC and RARβ2, respectively, and primary Gleason grade was detectable. GSTP1 methylation was also associated with extraprostatic tumor extension. Conclusion: GSTP1, APC, RARβ2 and PITX2 methylation occur frequently in prostate cancer, making these markers sensitive tools for the detection of neoplastic lesions in the prostate. For RARβ2, the results suggest a kind of methylation field effect which could be helpful for the detection of prostate cancer. Larger studies are necessary to investigate a potential correlation of GSTP1, RARβ2 and APC hypermethylation with tumor aggressiveness.

DNA Methylation Changes Correlate with Gleason Score and Tumor Stage in Prostate Cancer

“…Consistent with most previous observations in prostate tumor tissue and blood ( Jeronimo et al, 2004;Yegnasubramanian et al, 2004;Reibenwein et al, 2007;Sunami et al, 2009;Steiner et al, 2010), we found that elevated DNA methylation levels in prostate tumor tissues were related to worse clinicopathological outcomes. Specifically, GSTP1, p16 (CDKN4A), and APC methylation levels were significantly associated with higher Gleason score.…”

ID4 is frequently downregulated and partially hypermethylated in prostate cancer

“…Secondly, all three techniques used in our study identified weak ID4 methylation in benign prostatic tissues. Most likely, this observation may reflect an epigenetic field effect changing methylation [25,26], imprinting [27] and expression [28,29] of certain genes in cancer-carrying prostates. This field change could reflect morphologically inconspicuous tumor cells, changes in normal cells elicited by factors emanating from the actual cancer or a preneoplastic stage pervading the aging organ [30].…”

Role of Glutathione-S-Transferase P1 Hypermethylation in Molecular Detection of Prostate Cancer

“…Prostate tissue biopsy was able to detect GSTP1 methylation in 70.5% to 94% of PCa patients (Goessl et al, 2000;Jer-ó nimo et al, 2002;Steiner et al, 2010), with the variation between studies mostly due to variation in DNA methylation detection techniques.…”